1. Field of the Invention
The present invention generally relates to a family of allosteric effectors of hemoglobin and more specifically to chirality affects of allosteric effectors where the chiral carbon has a substituted carbon ring, a heteroatom ring, or different substituents. The invention includes several new potent enantiomers that are superior than their racemic mixture and other enantiomeric isomer, possessing different degrees of allosteric potency.
2. Background Description
Human hemoglobin (Hb) is a tetrameric allosteric protein comprised of two alpha and two beta chains and functions to deliver oxygen from the lungs to the many tissues of the body. The four subunits are arranged around a molecular two fold axis creating a central water cavity. As an allosteric protein, Hb exists in an equilibrium between two states, the relaxed (R) or oxy-state and the tense (T) or deoxy-state. In the oxy-state, the water cavity is narrow and the subunits have fewer and weaker bonds between them (i.e., relaxed). However, in the deoxy-state, the water cavity is larger, and the subunits are tightly tethered together by salt bridges (i.e., tense). The allosteric equilibrium can be influenced by allosteric modifiers. Such molecules can increase the oxygen affinity of Hb shifting the allosteric equilibrium toward oxy-Hb or decrease the affinity of oxygen, shifting the equilibrium to the deoxy-Hb. Modifiers that decrease the oxygen affinity act by adding constraints to the T-state. Oxygen affinity decreasing agents have several potential applications including radiosensitization of tumors, enhancement of oxygen delivery to hypoxic and ischemic tissues, and shelf-life prolongation of stored blood.
The gap between the β subunits is wide enough for 2,3-diphosphoglycerate (2,3-DPG), a naturally occuring allosteric modifier, to dock in and bind, forming additional salt bridges that further stabilize the deoxy state. Therefore, compounds that lower the affinity of oxygen for Hb do so by strengthening the existing salt bridges or by adding new ones to the tense state.
Several synthetic agents have been, reported to lower the affinity of oxygen for Hb. In the search for an antisickling agent, Abraham and coworkers discovered the antilipidemic drug, clofibric acid, that lowered the oxygen affinity of Hb. Perutz and Poyart followed with a report that bezafibrate, another antilipidemic agent, was also a right-shifting compound, more potent than DPG and clofibric acid. Lalezari and coworkers demonstrated that shortening the four atom bridge to a three atom urea bridge produced even more potent allosteric modifiers, but their potential as clinical agents was limited due to loss of activity in the presence of serum albumin.
It has been proposed that influencing the allosteric equilibrium of hemogobin is a viable avenue of attack for treating diseases. The conversion of hemoglobin to a low affinity state is believed to have general utility in a variety of disease states where tissues suffer from low oxygen tension, such as ischemia and radio sensitization of tumors. Several synthetic compounds have been identified which have utility in the allosteric regulation of hemoglobin and other proteins.